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Blood. 2012 Dec 6;120(24):4829-39. doi: 10.1182/blood-2012-06-434894. Epub 2012 Oct 16.

CaMKII γ, a critical regulator of CML stem/progenitor cells, is a target of the natural product berbamine.

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1
Department of Hematology, Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Hangzhou, China.

Abstract

Bcr-Abl tyrosine kinase inhibitors (TKIs) have been a remarkable success for the treatment of Ph(+) chronic myeloid leukemia (CML). However, a significant proportion of patients treated with TKIs develop resistance because of leukemia stem cells (LSCs) and T315I mutant Bcr-Abl. Here we describe the unknown activity of the natural product berbamine that efficiently eradicates LSCs and T315I mutant Bcr-Abl clones. Unexpectedly, we identify CaMKII γ as a specific and critical target of berbamine for its antileukemia activity. Berbamine specifically binds to the ATP-binding pocket of CaMKII γ, inhibits its phosphorylation and triggers apoptosis of leukemia cells. More importantly, CaMKII γ is highly activated in LSCs but not in normal hematopoietic stem cells and coactivates LSC-related β-catenin and Stat3 signaling networks. The identification of CaMKII γ as a specific target of berbamine and as a critical molecular switch regulating multiple LSC-related signaling pathways can explain the unique antileukemia activity of berbamine. These findings also suggest that berbamine may be the first ATP-competitive inhibitor of CaMKII γ, and potentially, can serve as a new type of molecular targeted agent through inhibition of the CaMKII γ activity for treatment of leukemia.

PMID:
23074277
PMCID:
PMC4507036
DOI:
10.1182/blood-2012-06-434894
[Indexed for MEDLINE]
Free PMC Article

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